There have been many attempts to ease the difficulty of healing damaged articular cartilage, since, once damaged, the articular cartilage cannot be regenerated into original tissue. Currently, for advanced degenerative arthritis, the standardized treatment is to remove the affected cartilage and bone and replace them with an artificial joint consisting of a metal(s) and a polyethylene, but the durability of such an artificial joint becomes an issue when it is implanted into a relatively young patient in his/her 60s or younger. The development of damaged cartilage is caused by osteoarthritis which brings a traumatic loss or gradual destruction of articular cartilage tissue, and, despite the high incidence thereof, the regeneration of damaged cartilage into original tissue thereof, i.e., hyaline cartilage, is difficult, and not much is known about the molecular mechanism of cartilage regeneration.
Conventional methods of treating a damaged joint include medication, autologous chondrocyte implantation, bone marrow drilling, artificial joint replacement, and the like. Among them, conservative treatment such as medication is limited to the restoration of a limited number of functions by alleviating symptoms, and autologous chondrocyte implantation used for treating a traumatic loss of articular cartilage causes damage in the donor site by harvesting a bone-cartilage piece therefrom and the amount collectable is limited. In addition, bone marrow drilling performed for osteoarthritis with moderate progression results in the regeneration of fibrous cartilage instead of the original cartilage tissue, i.e., hyaline cartilage, thus generating poor clinical results. Moreover, the durability of an artificial joint can also be an issue when the artificial joint is implanted into a young patient, although artificial joint replacement is currently the standardized treatment for advanced osteoarthritis.
To solve aforementioned problems, stem cells offering the benefit of self-replication, differentiation into various tissues, and easy harvesting of a large amount without causing the functional disability of the donor site were recently recognized as ideal sources of cells for cell therapy and are actively researched. However, still, there is a lack of clear knowledge of cartilage formation in terms of the factors, environment, and the like.
Stem cells for articular cartilage regeneration are characterized by a self-proliferation ability and a differentiation ability, i.e., an ability to be differentiated into cells constituting a particular tissue, and have been recently proposed as new sources of cells to be applied in articular cartilage treatment. Therefore, theoretically, such stem cells may be used to ease the limitations that conventional cell therapy using chondrocytes have and to treat the overall degeneration and damage of articular cartilage. In addition, the use of adult mesenchymal stem cells and mesenchymal progenitor cells are free from ethical issues and allograft rejection.
However, since not all adult mesenchymal stem cells completely differentiate into chondrocytes at the same time, ways to induce their differentiation into homogeneous chondrocytes are needed, and, for the differentiation of mesenchymal stem cells into cartilage, ways to inhibit cell hypertrophy, which is a prodromal sign of the apoptosis of cells induced into cartilage and of bone differentiation, by precisely controlling the same is strongly needed to apply chondrocytes differentiated from stem cells for cell therapy.
The hypertrophy of chondrocytes is a process that occurs during ontogenesis or in every stage of chondrocyte destruction and bone formation during endochondral ossification in a growth plate and is always observed during the maturation of chondrocytes other than articular chondrocytes. However, since cartilage tissue engineering aims to regenerate articular cartilage, regenerated cartilage should exhibit the properties of hyaline cartilage found in a normal joint and should not experience hypertrophy.
The parathyroid hormone-related protein (PTHrP) is a peptide that is involved in chondrocyte proliferation and maturation in a growth plate, and is secreted within cartilage surrounding a joint and diffuses to act on a prehypertrophic chondrocyte in a growth plate, thereby inhibiting the formation of the Indian hedgehog (IHH) protein that promotes chondrocyte maturation, thus maintaining the phenotype of a chondrocyte and inhibiting chondrocyte hypertrophy.
However, until now, any reaction mechanism of IHH protein generation inhibition by PTHrP has not been explained in terms of a precise molecular biological mechanism.